Phenotypes of APOL1 High-Risk Status Subjects
Authors: Jeffrey B. Kopp, Teruhiko Yoshida
Journal: Journal of the American Society of Nephrology (2023)

In this issue of the JASN, Elliott and colleagues report the clinical characteristics of 239 patients harboring two apolipoprotein L1 (APOL1) kidney risk alleles, perhaps the largest such series to date.1 Two groups first reported coding variants of the gene in 2010.2,3 These variants account for a large proportion of excess primary glomerular disease among individuals with recent sub-Saharan ancestry (in the past 1000 years or so), as recently reviewed.4,5 High-risk status is defined as carrying two APOL1 risk alleles. APOL1 variant G1 substitutes two amino acids, serine to glycine at position 342 and isoleucine to methionine at position 384. Variant G2 deletes asparagine 388 and tyrosine 389. Likely, 13% of the 41 million African American individuals carry two APOL1 risk alleles, placing approximately five million individuals at increased risk for kidney disease on this genetic basis. The number who will develop APOL1-related kidney disease is not known, but may be on the order of one million individuals. APOL1 risk genotypes are associated with increased propensity to develop various kidney diseases (Table 1). These include FSGS (odds ratio [OR], 17),6 such as HIV-associated nephropathy (OR as high as 29) and hypertension misattributed kidney disease (manifesting histologically as arterionephrosclerosis [OR, 7]).4 Individuals with APOL1 high-risk status are more likely to have rapid progression of kidney disease than others with similar diagnoses. This is true for the diseases listed above as well as for lupus nephritis5 and sickle cell nephropathy.7 Progressive loss of kidney function may occur even in patients who respond to therapy with some reduction in proteinuria. In addition, recipients of kidneys from deceased donors who had APOL1 risk genotypes have earlier allograft loss compared with recipients of other kidneys. Estimates of lifetime kidney disease risk for APOL1 high-risk status individuals are 4% for FSGS are 4% and 50% for those with untreated HIV infection.6 Table 1 - Kidney diseases and associations of apolipoprotein L1 high-risk status Disease ORs or Phenotype HIVAN 27 (the United States), 89 (South Africa) FSGS 17 Hypertension-attributed ESKD 7 Lupus nephritis ESKD 2.7 Pre-eclampsia 3.6 AKI 2.0 Membranous nephropathy Faster progression Shown are kidney diseases associated with apolipoprotein L1 kidney risk alleles and the odds ratio for two risk alleles compared with 0 or 1 risk allele. For HIV-associated nephropathy in South Africa, a single-risk allele is also associated with an increased risk for kidney disease, with odds ratios shown. OR, odds ratio; HIVAN, HIV-associated nephropathy. Elliott and colleagues describe the key clinical features of APOL1 variant–associated glomerular disease, drawing upon their experience comparing 239 cases with high-risk genotypes (carrying two APOL1 risk alleles) with 1187 ancestry-matched cases. Not surprisingly, the most common glomerular diseases were FSGS and hypertension-attributed kidney disease. The authors report an estimated glomerular rate decline of 6.55 versus 3.63 ml/min per 1.73 m2 for high-risk and low-risk subjects, respectively. Over the long run, the risk of kidney failure was greater among high-risk individuals, with a hazard ratio of 1.58. Perhaps less well known is the role of APOL1 variants in lupus nephritis, which has a relative risk for kidney failure of 2.51 for high-risk compared with low-risk individuals. Other reported characteristics of APOL1 kidney disease, compared with other forms of FSGS, are in line with previous reports, such as younger age at onset (45 versus 56 years). These data are similar to previous reports of ORs for individuals carrying two APOL1 risk alleles for various conditions (Table 1). Individuals with kidney disease and APOL1 high-risk status may tend to progress more quickly to ESKD compared with individuals with the same diagnosis but not the risk variants because of the multiple APOL1-associated cell injury pathways. These six pathways have been investigated in cell culture and/or animal models and may or may not be relevant to human disease. They are formation of channels or pores in intracellular membranes, mitochondrial dysfunction, endolysosomal dysfunction, activation of NLRP3 inflammasomes, activation of αvβ3 integrin, and activation of protein kinase R. One of the most interesting findings is that individuals with APOL1 high-risk status are more likely to have rare missense mutations in the inflammasome pathways. Inflammasomes are components of the innate immune response. This arm of immunity is considered to be evolutionarily older because it has roots in early single-celled eukaryotes such as amebae, perhaps enabling them to distinguish food and other amebae.8 By contrast, the antibodies and T lymphocytes of the adaptive immune response are shaped by exposure to organisms and molecules over a lifetime. The adaptive immune response, which includes B and T lymphocytes, requires exposure to an antigen; the innate immune response does not require such priming. Finding excess rare variants in APOL1 high-risk cases in another arm of the innate immune system suggests a novel three-hit model: APOL1 high-risk status (genetic), additional innate immune system variants (genetic), and an exogenous factor. The exogenous factor might stimulate APOL1 gene expression, such as increased interferon levels in response to chronic viral infection from HIV, severe acute respiratory syndrome coronavirus 2, or viral hepatitis or interferon therapy. Identification of these additional innate immune variants and their roles in APOL1 pathogenesis might inform development of novel therapeutic approaches. Fortunately, therapies that directly target APOL1 are currently undergoing testing and may be safe for individuals living outside of trypanosomal endemic regions. These therapies include a Phase 1 study of Janus kinase inhibition using baricitinib at Duke University to reduce APOL1 gene expression and a multicenter, Phase 2/3 randomized adaptive study of VX-147, a small molecule inhibitor of APOL1 function that will enroll 260 subjects (a follow-on to a previous study with the same agent), developed by Vertex Pharmaceuticals, Boston, MA. In the next few years, more effective therapies to slow and perhaps halt the progression of the APOL1 nephropathies may emerge. In conclusion, in the 13 years since the identification of the APOL1 renal risk variants, there has been substantial progress in characterizing clinical phenotypes; educating clinicians, patients, and families; and now developing novel therapies that directly target the APOL1 variant proteins.